AIMS/HYPOTHESIS: Sirtuin (SIRT)3 is a mitochondrial protein deacetylase that regulates reactive oxygen species (ROS) production and exerts anti-inflammatory effects. As chronic inflammation and mitochondrial dysfunction are key factors mediating pancreatic beta cell impairment in type 2 diabetes, we investigated the role of SIRT3 in the maintenance of beta cell function and mass in type 2 diabetes. METHODS: We analysed changes in SIRT3 expression in experimental models of type 2 diabetes and in human islets isolated from type 2 diabetic patients. We also determined the effects of SIRT3 knockdown on beta cell function and mass in INS1 cells. RESULTS: SIRT3 expression was markedly decreased in islets isolated from type 2 diabetes patients, as well as in mouse islets or INS1 cells incubated with IL1β and TNFα. SIRT3 knockdown in INS1 cells resulted in lowered insulin secretion, increased beta cell apoptosis and reduced expression of key beta cell genes. SIRT3 knockdown also blocked the protective effects of nicotinamide mononucleotide on pro-inflammatory cytokines in beta cells. The deleterious effects of SIRT3 knockdown were mediated by increased levels of cellular ROS and IL1β. CONCLUSIONS/ INTERPRETATION: Decreased beta cell SIRT3 levels could be a key step in the onset of beta cell dysfunction, occurring via abnormal elevation of ROS levels and amplification of beta cell IL1β synthesis. Strategies to increase the activity or levels of SIRT3 could generate attractive therapies for type 2 diabetes.
AIMS/HYPOTHESIS: Sirtuin (SIRT)3 is a mitochondrial protein deacetylase that regulates reactive oxygen species (ROS) production and exerts anti-inflammatory effects. As chronic inflammation and mitochondrial dysfunction are key factors mediating pancreatic beta cell impairment in type 2 diabetes, we investigated the role of SIRT3 in the maintenance of beta cell function and mass in type 2 diabetes. METHODS: We analysed changes in SIRT3 expression in experimental models of type 2 diabetes and in human islets isolated from type 2 diabeticpatients. We also determined the effects of SIRT3 knockdown on beta cell function and mass in INS1 cells. RESULTS:SIRT3 expression was markedly decreased in islets isolated from type 2 diabetespatients, as well as in mouse islets or INS1 cells incubated with IL1β and TNFα. SIRT3 knockdown in INS1 cells resulted in lowered insulin secretion, increased beta cell apoptosis and reduced expression of key beta cell genes. SIRT3 knockdown also blocked the protective effects of nicotinamide mononucleotide on pro-inflammatory cytokines in beta cells. The deleterious effects of SIRT3 knockdown were mediated by increased levels of cellular ROS and IL1β. CONCLUSIONS/ INTERPRETATION: Decreased beta cell SIRT3 levels could be a key step in the onset of beta cell dysfunction, occurring via abnormal elevation of ROS levels and amplification of beta cell IL1β synthesis. Strategies to increase the activity or levels of SIRT3 could generate attractive therapies for type 2 diabetes.
Authors: Hongying Yang; Tianle Yang; Joseph A Baur; Evelyn Perez; Takashi Matsui; Juan J Carmona; Dudley W Lamming; Nadja C Souza-Pinto; Vilhelm A Bohr; Anthony Rosenzweig; Rafael de Cabo; Anthony A Sauve; David A Sinclair Journal: Cell Date: 2007-09-21 Impact factor: 41.582
Authors: P Marchetti; M Bugliani; R Lupi; L Marselli; M Masini; U Boggi; F Filipponi; G C Weir; D L Eizirik; M Cnop Journal: Diabetologia Date: 2007-09-30 Impact factor: 10.122
Authors: Sadhana A Samant; Hannah J Zhang; Zhigang Hong; Vinodkumar B Pillai; Nagalingam R Sundaresan; Donald Wolfgeher; Stephen L Archer; David C Chan; Mahesh P Gupta Journal: Mol Cell Biol Date: 2013-12-16 Impact factor: 4.272
Authors: Di Shao; Jessica L Fry; Jingyan Han; Xiuyun Hou; David R Pimentel; Reiko Matsui; Richard A Cohen; Markus M Bachschmid Journal: J Biol Chem Date: 2014-01-22 Impact factor: 5.157